Regulation of Plasmid Specified MLS-Resistance in Bacillus subtilis by Conformational Alteration of RNA Structure

  • D. Dubnau
  • G. Grandi
  • R. Grandi
  • T. J. Gryczan
  • J. Hahn
  • Y. Kozloff
  • A. G. Shivakumar


Resistance to the macrolide-lincosamide-streptogramin B (MLS) group of antibiotics, often mediated by plasmids, is widespread among clinically isolated strains of Staphylococcus and Strepto-coccus (1–5). The mechanism of resistance to these inhibitors of protein synthesis has been elucidated by B. Weisblum and his colleagues (6–8). MLS-resistance is associated with the presence of 1additional methyl groups (as N6, N6-dimethyl adenine) on 23S rRNA. This modification reduces the ribosomal affinity for the MLS antibiotics. In many cases exposure to a subinhibitory concentration of erythromycin (Em), results in induction of resistance to elevated levels of antibiotic. Although only Em and a few closely related macrolides like oleandomycin (Om) act as inducers, cultures exposed to these drugs acquire resistance to the entire range of MLS antibiotics. We will deal in this report with the MLS resistance specified by the 3.5 kb plasmid pE194. This entity was isolated from Staphylococcus aureus (9) and then transferred to Bacillus subtilis (10). All of our work has been carried out in the latter organism.


Amino Acid Peptide Amino Acyl tRNA rRNA Methylation Tandem Repeat Amino Acid Plasmid pE194 
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  1. 1.
    Clewell, D.B. and Franke, A.E. (1974) Antimicrob. Ag. Chemother. 5, 534–537.CrossRefGoogle Scholar
  2. 2.
    Courvalin, P.M., Carlier, C. and Chabbert, Y.A. (1972) Ann. Inst. Pasteur (Paris) 123, 755–759.Google Scholar
  3. 3.
    Horodniceanu, T., Bouanchaud, D.H., Bieth, G. and Chabbert, Y.A. (1976) Antimicrob. Ag. Chemother. 10, 795–801.CrossRefGoogle Scholar
  4. 4.
    Jacobs, M.R., Koornhof, H.J., Robins, O. Browne, R.M., Stevenson, C.M., Vermaak, Z.A., Freiman, I., Miller, G.B., Witcomb, M.A., Isaacson, M., Ward, J.I. and Austrian, R. (1978) New Engl. J. Med. 299, 735–740.PubMedCrossRefGoogle Scholar
  5. 5.
    Otaya, H. (1971) In Drug Action and Drug Resistance in Bacteria (S. Mitsuhashi, ed.) University Park Press, Baltimore.Google Scholar
  6. 6.
    Lai, C.-J. and Weisblum, B. (1971) Proc. Nat. Acad. Sci. USA 68, 856–860.PubMedCrossRefGoogle Scholar
  7. 7.
    Lai, C.-J., Dahlberg, J.E. and Weisblum, B. (1973) Biochemistry 12, 457–460.PubMedCrossRefGoogle Scholar
  8. 8.
    Lai, C.-J., Weisblum, B., Fahnestock, S.R. and Nomura, M. (1973) J. Mol. Biol. 74, 67–72.PubMedCrossRefGoogle Scholar
  9. 9.
    Iordanescu, S. (1976) Arch. Roum. Path. Exp. Microbiol. 35, 111–118.PubMedGoogle Scholar
  10. 10.
    Weisblum, B., Graham, M.Y., Gryczan, T. and Dubnau, D. (1979) J. Bacteriol. 137, 635–643.PubMedGoogle Scholar
  11. 11.
    Shivakumar, A.G., Hahn, J. and Dubnau, D. (1979) Plasmid 2, 279–289.PubMedCrossRefGoogle Scholar
  12. 12.
    Shivakumar, A.G., Gryczan, T.J., Kozlov, Y.I. and Dubnau, D. (1980a) Molec. gen. Genet. 179, 241–252.PubMedCrossRefGoogle Scholar
  13. 13.
    Gryczan, T.J., Grandi, G., Hahn, J., Grandi, R. and Dubnau, D. (1980) Nucl. Acids Res. 8, 6081–6097.PubMedCrossRefGoogle Scholar
  14. 14.
    Reeve, J.N., Mendelson, N.H., Coyne, S.I., Hailock, L.L. and Cole, R.M. (1973) J. Bacteriol. 114, 860–873.PubMedGoogle Scholar
  15. 15.
    Shivakumar, A.G., Hahn, J., Grandi, G., Kozlov, Y. and Dubnau, D. (1980b) Proc. Nat. Acad. Sci. USA 77, 3903–3907.PubMedCrossRefGoogle Scholar
  16. 16.
    Tipper, D.J., Johnson, C.W., Ginther, C.L., Leighton, T. and Wittman, H.G. (1977) Molec. gen. Genet. 150, 147–159.PubMedCrossRefGoogle Scholar
  17. 17.
    Contente, S. and Dubnau, D. (1979b) Plasmid 2, 555–571.PubMedCrossRefGoogle Scholar
  18. 18.
    Rosenberg, M. and Court, D. (1979) Ann. Rev. Genet. 13, 319–353.PubMedCrossRefGoogle Scholar
  19. 19.
    Shine, J. and Dalgarno, L. (1974) Proc. Nat. Acad. Sci. USA 71, 1342–1346.PubMedCrossRefGoogle Scholar
  20. 20.
    Shine, J. and Dalgaron, L. (1975) Nature 254, 34.PubMedCrossRefGoogle Scholar
  21. 21.
    Sprague, K.U., Steitz, J.A., Grenley, R.M. and Stocking, C.E. (1977) Nature 267, 462.PubMedCrossRefGoogle Scholar
  22. 22.
    Woese, C, Sogin, M., Stahl, D., Lewis, B.J. and Bowen, L. (1976) J. Mol. Evol. 7, 197.PubMedCrossRefGoogle Scholar
  23. 23.
    Barnes, W.M. (1978) Proc. Nat. Acad. Sci. USA 75, 4281–4285.PubMedCrossRefGoogle Scholar
  24. 24.
    Di Nocera, P.P., Blasi, F., Di Lauro, R., Frunzio, R. and Bruni, C.B. (1978) Proc. Nat. Acad. Sci. USA 75, 4276–4280.PubMedCrossRefGoogle Scholar
  25. 25.
    Gardner, J.F. (1979) Proc. Nat. Acad. Sci. USA 76, 1706–1710.PubMedCrossRefGoogle Scholar
  26. 26.
    Gemmill, R.M., Wessler, S.R., Keller, E.B. and Calvo, J.M. (1979) Proc. Nat. Acad. Sci. USA 76, 4941–4945.PubMedCrossRefGoogle Scholar
  27. 27.
    Zurawski, G., Brown, K., Killingly, D. and Yanofsky, C. (1978) Proc. Nat. Acad. Sci. USA 75, 4271–4275.PubMedCrossRefGoogle Scholar
  28. 28.
    Zurawski, G., Elseviers, D., Stauffer, G.V. and Yanofsky, C. (1978) Proc. Nat. Acad. Sci. USA 75, 5988–5992.PubMedCrossRefGoogle Scholar
  29. 29.
    Miller, J.H. (1974) Cell 1, 73–76.CrossRefGoogle Scholar
  30. 30.
    Steitz, J.A. (1979) In Biological Regulation and Development, Vol. 1. Gene Expression. (R.F. Goldberger, ed.) pp. 349–399. Plenum Press, New York.Google Scholar
  31. 31.
    Borer, P.N., Dengler, B. and Tinoco, Jr., I., Uhlenbeck, O.C. (1974) J. Mol. Biol. 86, 843–853.PubMedCrossRefGoogle Scholar
  32. 32.
    Tinoco, Jr., I., Borer, P.N., Dengler, B., Levine, M.D., Uhlenbeck, O.C., Crothers, D.M. and Gralla, J. (1973) Nature New Biology 246, 40–41.PubMedGoogle Scholar
  33. 33.
    Tai, P.-C., Wallace, B.J. and Davis, B.D. (1974) Biochemistry 13, 4653–4659.PubMedCrossRefGoogle Scholar
  34. 34.
    Pestka, S. (1974) Antimicrob. Ag. Chemother. 5, 255–267.CrossRefGoogle Scholar
  35. 35.
    Kubota, K., Okuyama, A. and Tanaka, N. (1972) BBRC 47, 1196–1202.PubMedGoogle Scholar
  36. 36.
    Mao, J.C.-H. and Robishaw, E.E. (1971) Biochemistry 10, 2054–2061.PubMedCrossRefGoogle Scholar
  37. 37.
    Pestka, S. (1977) In Molecular Mechanisms of Protein Biosynthesis (H. Weissbach and S. Pestka, eds.) pp. 467–553, Academic Press, New York.Google Scholar
  38. 38.
    Mao, J.C.-H. and Robishaw, E.E. (1972) Biochemistry 11, 4864–4872.PubMedCrossRefGoogle Scholar
  39. 39.
    Steitz, J.A. (1975) In RNA Phages (N.D. Zinder, ed.) pp. 319–352. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.Google Scholar
  40. 40.
    Cerna, J., Jonák, J. and Rychlík, I. (1971) Biochem. Biophys. Acta 240, 109–121.PubMedCrossRefGoogle Scholar
  41. 41.
    Dennis, P.P. and Fiil, N.P. (1979) J. Biol. Chem. 254, 7540–7547.PubMedGoogle Scholar
  42. 42.
    Fiil, N.P., Friesen, J.D., Downing, W.L., Dennis, P.P. (1980) Cell 19, 837–844.PubMedCrossRefGoogle Scholar
  43. 43.
    Ishihama, A., Fukuda, R., Kajitani, M. (1980) Molec. Gen. Genet. 179, 489–496.PubMedCrossRefGoogle Scholar
  44. 44.
    Lemaire, G., Gold, L. and Yarus, M. (1978) J. Mol. Biol. 126, 73–90.PubMedCrossRefGoogle Scholar
  45. 45.
    Fallon, A.M., Jinks, C.S., Strycharz, G.D. and Nomura, M. (1979) Proc. Nat. Acad. Sci. USA 76, 3411–3415.PubMedCrossRefGoogle Scholar
  46. 46.
    Dean, D. and Nomura, M. (1980) Proc. Nat. Acad. Sci. USA 77, 3590–3594.PubMedCrossRefGoogle Scholar
  47. 47.
    Yates, J.L. and Nomura, M. (1980) Cell 21, 517–522.PubMedCrossRefGoogle Scholar
  48. 48.
    Yates, J.L., Arfsten, A.E. and Nomura, M. (1980) Proc. Nat. Acad. Sci. USA 77, 1837–1841.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1981

Authors and Affiliations

  • D. Dubnau
    • 1
  • G. Grandi
    • 1
  • R. Grandi
    • 1
  • T. J. Gryczan
    • 1
  • J. Hahn
    • 1
  • Y. Kozloff
    • 1
  • A. G. Shivakumar
    • 1
  1. 1.Department of MicrobiologyThe Public Health Research Institute of the City of New York, Inc.New YorkUSA

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